Search PubMed⌕ Search

Biomedical subjects

J M DeSesso

Publications and source records attributed to J M DeSesso.

At least 19 recordsLinked to original sources
PubMed2001

Teratogen update: inorganic arsenic.

BACKGROUND: Inorganic arsenic has been used by many laboratories to study the pathogenesis of exencephaly in rodents. These studies, which used predominantly injection exposures, coupled with the paucity of epidemiology data, resulted in the erroneous inference that inorganic arsenic should be considered a human teratogen. METHODS: This study assembles and assesses literature analyses of older human and animal investigations together with the results of new experimental studies. These recent studies were performed according to modern regulatory guidelines, and relevant exposure routes (inhalation and ingestion) were used to evaluate the potential risk of developmental effects in humans. RESULTS: The existing epidemiological data are inadequate to support risk assessment because of the failure to confirm or measure arsenic exposure during early gestation and the deficiencies in accounting for potential confounding factors. The animal data revealed that inorganic arsenic caused malformations in offspring only when it was injected into the veins or peritoneal cavity of pregnant animals during early gestation. Exposure via inhalation or oral ingestion, even at concentrations that were nearly fatal to pregnant females, caused no arsenic-related malformations. CONCLUSIONS: Inorganic arsenic poses virtually no danger to developing offspring when maternal exposure occurs by relevant routes (oral and inhalation) at concentrations that are likely to be experienced in the environment or in the workplace.

Animals↗
PubMed2001

Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats.

Anatomical and physiological parameters of the gastrointestinal (GI) tract dramatically affect the rate and extent of absorption of ingested compounds. These parameters must be considered by nutritionists, pharmacologists and toxicologists when describing or modeling absorption. Likewise, interspecies extrapolation (e.g. from rat to human) requires species-to-species comparison of these parameters. The present paper (1) describes the alimentary canal and the barrier to absorption; (2) relates the major sites of absorption; (3) compares the dimensions and surface areas of human and rat intestinal tracts; (4) discusses motility of the gut and transit times through regions of the alimentary canal; (5) explains how luminal contents are altered by physical, chemical and metabolic processes; and (6) describes the flow of blood and lymph from the GI tract to the systemic circulation, including the enterohepatic circulation. Despite strong morphological similarities between humans and rats at the microscopic level, gross anatomical differences in the relative absorptive surface areas provide a basis for concluding that the human GI tract is capable of absorbing materials faster and to a greater extent than that of the rat. Differences in the environment of the GI lumen of the two species make it possible to infer which substances are more likely to be present in a dissolved/non-ionized state for each species. Taken together, these differences may be of sufficient magnitude to alter the assessment of risks/benefits for a given compound when those risks/benefits are based on interspecies extrapolations.

Animals↗
PubMed2000

Hydroxylamine moiety of developmental toxicants is associated with early cell death: a structure-activity analysis.

BACKGROUND: Cellular debris, an indicator of cell death, appears in limb buds of gestational day 12 rabbit embryos 4 hr after either a subcutaneous injection of hydroxyurea to pregnant rabbits or an injection of hydroxyurea into the exocoelomic cavities of the embryos. This episode of early cell death appears to be central to the teratogenic action of hydroxyurea. Several chemicals that are structurally related to hydroxyurea, and that possess a terminal hydroxylamine moiety (-NHOH), also produce limb abnormalities. METHODS: To investigate whether the hydroxylamine moiety is responsible for early cell death and, therefore, is likely to be associated with teratogenesis, five structurally related hydroxylamine-bearing chemicals (hydroxylamine hydrochloride, N-methylhydroxylamine hydrochloride, hydroxyurea, acetohydroxamic acid, and hydroxyurethane) were administered at equimolar doses to rabbits either by subcutaneous (8.55 mmol/kg) or intracoelomic (2.66 micromol/embryo) injection on gestational day 12. Five additional chemicals, structurally similar to the hydroxylamine-bearing compounds, but possessing a terminal amino group (-NH(2)) (ammonium hydroxide, methylamine, urea, acetamide, and urethane), were tested at equimolar or higher doses by an identical protocol. In a subsequent experiment, the antioxidant propyl gallate (3.0 mmol/kg or 1.30 micromol/embryo) was co-administered with the hydroxylamine-bearing compounds to determine its effect on early cell death. Embryos were harvested 4 or 8 hr after treatment and analyzed by light microscopy. RESULTS: Cellular debris was obvious in forelimb buds from embryos treated with the hydroxylamine-bearing compounds; however, none of the amino compounds produced an early episode of embryonic cell death. In all cases, the antioxidant propyl gallate prevented or delayed the early episode of cell death observed after treatment with the hydroxylamine-bearing compounds. CONCLUSIONS: These results are consistent with the concept that the rapidly occurring embryonic cytotoxicity induced by hydroxylamine-bearing compounds involves a free radical mechanism that requires the presence of a terminal hydroxylamine group for initiation.

Abnormalities, Drug-Induced↗
PubMed2000

Assessment of the carcinogenicity associated with oral exposures to hydrogen peroxide.

Concern regarding hydrogen peroxide (H(2)O(2)) carcinogenicity arises from its ability to act as a strong oxidizing agent. In short-term genotoxicity tests, H(2)O(2) has given predominantly positive results; however, these assays have been performed using either bacterial strains engineered to be exquisitely sensitive to oxidant damage, or mammalian cells deficient in antioxidant enzymes. Significantly, the addition of antioxidant protective measures (normally present in vivo) to these assay systems protects against H(2)O(2) genotoxicity. In most whole animal studies, H(2)O(2) exposure neither initiates nor promotes tumors. In mice, however, 0.4% H(2)O(2) in drinking water was reported to induce hyperplastic lesions of the duodenum and to erode areas in the glandular stomach epithelium. Owing to the chemistry of dilute H(2)O(2) solutions and the anatomy/physiology of the gastrointestinal tract, it is unlikely that orally ingested H(2)O(2) reaches the duodenum. Instead, greatly decreased water consumption and the resultant abrasion of the luminal lining on ingestion of pelleted dry rodent chow is the most likely cause of the observed gastric and duodenal lesions following H(2)O(2) administration in drinking water. Significantly, when hamsters received high doses of H(2)O(2) by gastric intubation (and water intake was not affected), the gastric and duodenal epithelia appeared normal. In-depth analysis of the available data supports the conclusion that oral ingestion of H(2)O(2) should not be considered a carcinogenic threat.

Administration, Oral↗
PubMed2000

Workshop to identify critical windows of exposure for children's health: cardiovascular and endocrine work group summary.

The work group on cardiovascular and endocrine effects was asked to review the current state of knowledge about children's windows of vulnerability to developmental toxicants and to recommend how that information may be used to improve risk assessment and public health. We considered differences between structural defects, where periods of vulnerability are rather well defined, and functional defects, where periods of vulnerability are quite elusive.

Cardiovascular System↗
PubMed1999

Apparent lability of neural tube closure in laboratory animals and humans.

Neural tube defects (NTDs), a set of structural abnormalities affecting the brain, spinal cord, and the skeletal and connective tissues that protect them, are common malformations among humans and laboratory animals. The embryogenesis of the neural tube is presented to convey the complexity of the phenomenon, the multiplicity of requisite cellular and subcellular processes, and the precise timing of events that must occur for successful neural tube development. Interruption, even transitory, of any of these intricate processes or disruption of an embryo's developmental schedule can lead to an NTD. The population distribution of human NTDs demonstrates that genetic predisposition functions in susceptibility to NTDs. Data from animal studies support these concepts. NTDs are common outcomes in developmental toxicity safety assessments, occurring among control and treated groups. Numerous agents have caused increased levels of NTDs in laboratory animals, and species with shorter gestational periods appear more prone to toxicant-induced NTDs than those with longer gestations. Data from post-implantation whole embryo culture, although not predictive of human risk, are useful in studying neurulation mechanisms and in demonstrating the importance of maintaining embryonic schedules of development. We conclude that the concept that NTDs are produced by only a few toxicants that selectively target the developing nervous system is untenable. Rather, the combination of the time in gestation that an agent is applied, its dose, and its ability to disrupt critical processes in neurulation leads to NTDs. We further conclude that, because of both the relatively high prevalence and the multifactorial nature of NTDs, the mere occurrence of an NTD is insufficient for inferring that the defect was caused by an exogenous agent.

Animals↗
PubMed1995

Embryotoxicity of free and liposome-encapsulated taxol in the chick.

Taxol, an inhibitor of microtubule disaggregation, is used in the therapy of breast, ovarian, and other human malignancies. The toxicity of taxol administration is due in part to the polyoxyethylated castor oil (Cremaphor) vehicle in which it is administered; taxol embryotoxicity appears also to be partially attributable to vehicle toxicity. Liposome encapsulation is a novel vehicle for drug administration. The administration of taxol encapsulated in liposomes was evaluated in the chick embryo. Albumen injections of taxol doses up to 30 micrograms/egg were used to characterize dose-response curves for free and liposome-encapsulated taxol, compared to liposome-only and saline-injected control eggs. Sixty percent embryotoxicity (death or malformation) occurred with taxol doses of 1.5 micrograms/egg. A 20-fold higher dose was necessary to produce the same degree of toxicity with liposome-encapsulated taxol. Curve-fitting equations were used to estimate median effective doses (ED50s) and slope functions of the dose response curves. The ED50 for taxol was more than an order of magnitude lower than that for liposome-encapsulated taxol. Estimated slope functions for the two dosage forms of taxol were the same, suggesting similar mechanisms of toxicity. The toxicity of liposomes alone was low.

Abnormalities, Drug-Induced↗
PubMed1994

Taxol and embryonic development in the chick.

Taxol, an inhibitor of microtubule disassembly, is currently under investigation in the therapy of several human cancers. The current investigation was undertaken to characterize potential taxol developmental toxicity in chicks. On one of days 1-4 of incubation, taxol was administered in dimethylsulfoxide (DMSO) or olive oil in a range of doses, the highest of which produced a high incidence of early embryo death. Production of gross structural malformations was sporadic and occurred in vehicle-treated as well as taxol-treated embryos. A more common manifestation of taxol toxicity was a syndrome of visceral abnormalities, including regression of the vitelline circulation, dilatation of the atria, and hemorrhage in the left side of the head and thorax, often with decreased eye pigmentation. Regardless of the day of treatment, this syndrome occurred at 4.5-5 days. To investigate the possibility that taxol induced its effect through disruption of angiogenesis in the vitelline circulation, filters soaked in taxol were applied to the margin of the germ disc. No inhibition of vessel development was demonstrated. We conclude that taxol decreases the viability of embryos and that this impairment of survival precludes the development of birth defects. Solvent toxicity is an important confounder in the investigation of taxol embryotoxicity.

Abnormalities, Drug-Induced↗
PubMed1993

Have animal data been used inappropriately to estimate risks to humans from environmental trichloroethylene?

Trichloroethylene (TCE) is widely viewed as an environmental hazard. Its major metabolite, chloral hydrate, is a currently used medicine. Regulation of TCE is based on a linear extrapolation from effects of high doses in rodents to risks for humans at low doses. However, metabolic, toxicologic, and epidemiologic data on trichloroethylene and chloral hydrate as well as water chlorination studies call this approach into question. The mechanism of carcinogenesis of TCE and chloral hydrate in rodents is nonlinear: very high doses, sufficient to cause cellular necrosis, are necessary. Malignancy arises from repeated cycles of necrosis and regeneration with the ultimate emergence of hyperplasia and then neoplasia. Metabolites of TCE, trichloroacetic acid and dichloroacetic acid, mediate this toxic effect of TCE. These chloroacetic acids also induce similar lesions in rodents given high doses of the medicine, chloral hydrate. Human epidemiologic data show no increase in mortality or malignancy from substantial chronic exposure to trichloroethylene. Chlorination of drinking water produces much higher levels of chloroacetic acids than could be obtained from metabolizing TCE under current regulations. We conclude that the assumptions underlying current regulations are not applicable to TCE. Instead of a straight-line extrapolation model, a threshold model may be more appropriate. The data suggest that it is possible to increase substantially the allowable trichloroethylene in drinking water without increasing health hazards.

Animals↗
PubMed1993

The relevance to humans of animal models for inhalation studies of cancer in the nose and upper airways.

While nasal cancer is relatively rare among the general population, workers in the nickel refining, leather manufacturing, and furniture building industries exhibit increased incidences of nasal cancer. To investigate the causes of nasal cancer and to design ameliorative strategies, an appropriate animal model for the human upper respiratory regions is required. The present report describes, compares, and assesses the anatomy and physiology of the nasal passages and upper airways of humans, rats, and monkeys for the purpose of determining a relevant animal model in which to investigate potential causes of nasal cancer. Based on the mode of breathing, overall geometry of the nasal passages, relative nasal surface areas, proportions of nasal surfaces lined by various epithelia, mucociliary clearance patterns, and inspiratory airflow routes, the rat, which is very different from humans, is a poor model. In contrast, the monkey exhibits many similarities to humans. Although the monkey does differ from humans in that it exhibits a more rapid respiratory rate, smaller minute and tidal volumes, larger medial turbinate, and a vestibular wing that creates an anterior vortex during inspiration, it offers a more appropriate model for studying the toxic effects of inhaled substances on the nasal passages and extrapolating the findings to humans.

Administration, Inhalation↗
PubMed1992

Methotrexate-induced developmental toxicity in rabbits is ameliorated by 1-(p-tosyl)-3,4,4-trimethylimidazolidine, a functional analog for tetrahydrofolate-mediated one-carbon transfer.

Dihydrofolate reductase reduces folic acid to tetrahydrofolate as a prerequisite to one-carbon metabolism, which is required for normal embryonic de novo DNA synthesis. The developmental toxicity of methotrexate (MTX) has been attributed to MTX's ability to inhibit the activity of dihydrofolate reductase and thereby indirectly suppress one-carbon metabolism. The compound 1-(p-tosyl)-3,4,4-trimethylimidazolidine (TTI), which is structurally unrelated to folate, reestablishes one-carbon metabolism by the biomimetic transfer of single carbon units. Whether the developmental toxicity of MTX is indeed caused via suppressed one-carbon metabolism was tested in New Zealand white rabbits following concurrent maternal treatment with MTX and TTI. TTI reduced MTX developmental toxicity judged by increased mean fetal body weights, decreased percentage of malformed fetuses, and reduced incidences of major malformations. Two doses of TTI (90 mg/kg, each) at 1 hr prior to and 1 hr after MTX also reduced the developmental toxicity, but was no more effective than the single-injection regimen. Treatment with TTI alone caused no developmental toxicity. Histologically, MTX caused enlarged intercellular spaces in limb bud mesenchyme that began at 6-8 hr and increased in size until 16 hr. Mesenchymal nuclei appeared basophilic, with angular contours. Pretreatment with TTI delayed MTX-induced histological changes until 20-24 hr after MTX in 36-50% of embryos and completely protected the remainder. The sequence of MTX-induced changes was not altered among affected embryos, although the severity of the lesions did not appear as great. Saline-only or TTI-only treatments caused no alterations in limb buds. These data are consistent with the concept that impaired one-carbon metabolism is indeed the fundamental process underlying MTX developmental toxicity.

Animals↗
PubMed1991

Amelioration by leucovorin of methotrexate developmental toxicity in rabbits.

Methotrexate (MTX) is lethal or teratogenic to embryos of all species tested. New Zealand white rabbit embryos are relatively resistant to the embryolethal effects of MTX. However, when pregnant does were injected iv with 19.2 mg MTX/kg on gestational day 12, virtually all surviving fetuses exhibited multiple malformations of the head, limbs, and trunk. MTX is a structural analogue of folic acid that competitively inhibits dihydrofolate reductase, thereby preventing formation of folinic acid and essentially stopping one carbon metabolism. One carbon metabolism is important in the synthesis of methionine, histidine, glycine, and purine bases that are required for the de novo synthesis of DNA. Presumably these metabolic effects of MTX relate directly to its mechanism of developmental toxicity. An ameliorative treatment has been tested utilizing i.v. injection of pregnant rabbits with leucovorin (LV), a close structural analogue of folinic acid (the product of the inhibited enzyme), at various times after MTX exposure. When LV was injected at times up to 24 hours after MTX fewer malformed fetuses resulted and the incidence of specific malformations was reduced. When given at times up to 20 hours after MTX administration, LV virtually eliminated the grossly apparent effects of MTX at term. In the forelimb bud, MTX increased the extracellular space surrounding limb bud mesenchymal cells within 8-10 hours; this process continued through 16 hours and remained unabated by 24 hours. Mesenchymal cell nuclei became hyperchromatic and pyknotic during this time period. By 24 hours, a moderate amount of cellular debris was observed in the mesenchymal compartment of limb buds from approximately one-third of the embryos examined. Endothelial cell nuclei of the limb bud vasculature did not exhibit the histopathological alterations observed in the mesenchymal cells. Limb buds from embryos injected with LV at times up to 6 hours after MTX were histologically normal. When LV treatment was delayed until 16 or 20 hours after MTX, mesenchymal nuclei regained normal appearance within 2 hours of treatment; further, the abnormally large intracellular space began to decrease during the next 4 hours. Cellular debris was not a prominent feature of limb buds from LV-treated embryos examined at any time. Embryos from rabbits injected with LV at 24 hours after MTX exhibited either typical MTX-induced lesions or a sequence of reparative events similar to those described for the 16 and 20 hour LV-treated embryos.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗
PubMed1990

The nature of the embryo-protective interaction of propyl gallate with hydroxyurea.

Hydroxyurea (HU) is a swiftly acting cytotoxic teratogen and an inhibitor of DNA synthesis. Within 2 h of maternal treatment, HU causes necrosis in proliferating tissues of rabbit embryos on gestational day 12. Co-administration of the antioxidant propyl gallate (PG) delays the onset of necrosis until 6 h and ameliorates the teratogenic effects seen at term. Since HU also causes a rapid, profound decrease in uterine blood flow in pregnant rabbits, it is necessary to determine whether HU and PG interact within the pregnant female or within the embryo. In order to establish that the site of HU-PG interaction is embryonic, HU, PG, HU-PG, or vehicle was injected directly into implantation sites. When embryos were examined microscopically at 4 h, necrosis was observed only in the HU-treated embryos, indicating that the palliative interaction between HU and PG takes place within the embryo. To resolve whether the alleviation of HU-induced embryotoxicity was due to decreased HU levels within HU-PG embryos, HU concentrations were measured in embryos from HU-and HU-PG-treated maternal rabbits at 15 min to 8 h post injection. The HU levels of the two groups differed significantly only at 4 h. The rates of uptake during the linear phase (times from 15 min to 3 h) did not differ. When HU concentration was plotted versus time, measurements of the areas under the curve also did not differ. To determine whether PG alters the HU-induced inhibition of DNA synthesis, 3H-thymidine incorporation into embryonic DNA was assayed at 2 h after HU, HU-PG, or vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1990

Ethoxyquin and nordihydroguaiaretic acid reduce hydroxyurea developmental toxicity.

Hydroxyurea (HU) is a potent teratogen that causes a characteristic, rapidly occurring episode of embryonic cell death 2 to 4 h after subcutaneously injecting 650 mg/kg of HU into pregnant New Zealand White rabbits on gestational day 12. Previous studies documented the ability of the phenolic antioxidant, propyl gallate, to delay the onset of embryonic cell death and to decrease the number and severity of defects seen at term. The present study investigated the ability of the structurally different antioxidants, ethoxyquin (ETX) and nordihydroguaiaretic acid (NDGA), to also ameliorate HU developmental toxicity. Injection of pregnant rabbits with either ETX or NDGA at 950 mg/kg, 15 to 30 min prior to HU injection, resulted in reduced developmental toxicity seen at term. The reduction was manifested by fewer malformed fetuses with increased body weights compared with fetuses from HU-only treated litters, greatly reduced incidences of specific malformations, and diminished severity of some HU-induced defects. Microscopic analysis of HU, HU-ETX, and HU-NDGA embryos was performed at 4 or 8 h after treatment. HU caused cell death in the limb bud mesenchyme, clearly evident at 4 h. In contrast, HU-NDGA embryos exhibited no signs of cell death until 8 h after treatment. Although most HU-ETX embryos exhibited little or no cell death at 4 h after treatment, in about 20% the level of cell death was indistinguishable from that in HU-treated embryos. The amelioration of HU developmental toxicity in the present study is consistent with the results of previous studies utilizing propyl gallate. The results suggest that the antioxidant properties of these substances interfere with the rapidly occurring toxic effects of HU and that this may account for amelioration of HU developmental toxicity.

Abnormalities, Drug-Induced↗
PubMed1990

Developmental toxicity of hydroxylamine: an example of a maternally mediated effect.

Hydroxylamine (HA) is an important reducing agent that is used in several industries. HA is a moderate irritant and a powerful inducer of methemoglobinemia. HA has been shown to react readily with DNA in vitro. Several chemical derivatives of HA are potent developmental toxicants, whereas HA has been reported to cause no developmentally toxic effects. Since HA and its developmentally toxic derivatives share the presence of a terminal hydroxylamine functional group (-NHOH), and since that functional group has been proposed to be the biologically active portion of the molecule, it was deemed appropriate to re-examine the possible developmental toxicity of HA. Subcutaneous or intravenous injection of pregnant rabbits with 50-650 mg HA.HCl/kg on gestational day 12 caused the death or sacrifice of all rabbits within 30 hours. All maternally injected rabbits exhibited severe cyanosis, presumably due to methemoglobinemia. Histological examination of embryos revealed alterations of the cardiovascular system at 5 hours, but an absence of cell death in limb buds. At 8 hours, all embryos were dead. These effects appear to be secondary to the observed cyanosis in the maternal animals. In order to circumvent the powerful methemoglobinemia-inducing properties of HA, intracoelomic injections of 25-200 micrograms HA.HCl in 5-40 microliters of saline were made directly into the chorionic cavity of developing rabbit embryos, thereby bypassing the maternal system. Controls received similar volumes of saline. At doses of greater than or equal to 75 micrograms, HA.HCl killed 91 percent of injected embryos; among survivors, all exhibited reduced birth weights and 2/5 exhibited malformations in the craniofacial region and sternum. At doses of 25-50 micrograms, HA.HCl caused increased resorptions compared with controls; however, surviving fetuses displayed neither malformations nor reduced birth weights. Histological analysis at 4 hours after injection revealed cellular debris in the limb buds; when the antioxidant propyl gallate was co-administered with HA, cellular debris was absent at 4 hours. It is concluded that although HA is a directly acting developmental toxicant if it reaches the embryo, the observed embryolethality seen after subcutaneous injection of pregnant animals is a consequence of the powerful maternal toxicity of HA.

Animals↗
PubMed1989

Lectin teratogenesis. II: Demonstration of increased binding of concanavalin A to limb buds of rabbit embryos during the teratogenically sensitive period.

The plant lectin concanavalin A (con A) causes malformations of rabbit embryos when 160 micrograms (in 40 microliter) are injected into the exocoelom on gestational days 12-15 but does not cause malformations on days 10-11. The purpose of this study was to investigate the mechanism for increased susceptibility of day 12-15 embryos to con A teratogenicity. Light microscopy of day 11 embryos 15-20 hr after treatment with con A revealed no observable difference from controls. Day 13 embryos at similar times exhibited limb buds with large areas that were denuded of ectoderm. Concurrent addition of alpha-methyl-D-mannoside (alpha MM), a specific inhibitor of con A, to the injection solution of day 13 embryos resulted in limb buds that appeared normal. The regions of con A binding to day 11 and day 13 embryos were visualized through epifluorescent microscopy of untreated embryos stained with fluorescein-labelled con A. Day 11 embryos exhibited moderate fluorescence on the surface of limb buds and the pericardial region. Day 13 embryos exhibited strong fluorescence of limb bud surfaces; the pericardial region remained moderately fluorescent. Addition of alpha MM to the incubation medium resulted in no fluorescence above background. Visualization of con A receptors was accomplished by ultrastructural analysis of forelimb buds stained with ferritin-labelled con A. Ferritin label was observed only on the surfaces of the ectoderm and was sparse over all regions of day 11 limb buds. In contrast, ferritin label was moderately heavy in all regions of the day 13 limb buds. No labelling occurred when the ferritin-labelled con A was preincubated with alpha MM. These observations indicate that the number of exposed con A receptors on limb buds of teratogenically sensitive embryos (day 13) is increased, compared with the number of exposed receptors on limb buds of younger, insensitive (day 11) embryos. The increased number of exposed con A receptors on limb buds during the teratogenically sensitive period provides not only increased binding of the lectin to sensitive embryos but also a potential mechanism for the anomalous attachment of distal regions of the limb buds to the body wall.

Animals↗
PubMed1987

Maternal factors in developmental toxicity.

The maternal organism provides the developing embryo with its physical environment, nutrients, and a mechanism for eliminating metabolic wastes. Since the physiological state of the pregnant female affects her ability to provide those requirements for the developing embryo, it is not surprising that there are maternal factors that can affect the wellbeing of the embryo. Extremes of maternal age in both humans and animals have been implicated in growth retardation, as well as autosomal trisomies. The influence of maternal size on fetal size is more pronounced among larger species with longer gestation periods such as humans and domestic animals. A clear relationship between the parity of the mother and potential developmental toxicity in humans has not been established due to the confounding influences of maternal age. Among laboratory rodents, however, it appears that offspring of multiparous animals are at increased risk of developmental toxicity. A variety of infectious agents, particularly viruses, have either been demonstrated or implicated as causes of developmental toxicity. In addition, hyperthermia is a possible confounding factor inherent with maternal infection. Although under experimental conditions hyperthermia is teratogenic in laboratory animals, a causative role for transient hyperthermia, which occurs during febrile states concomitant with infections, cannot be clearly established. Chronic maternal vascular disease states including essential hypertension, heart disease, or diabetes mellitus are likely to contribute to uteroplacental insufficiency and developmental toxicity. Poor maternal nutrition among humans contributes to growth retardation, but not to malformations. The production of "abnormal" maternal antibodies, such as are present in Rh incompatibility, can cause fetal wastage. An important maternal factor in humans is uteroplacental insufficiency, which can occur in normal states like twinning, as well as in abnormal conditions including reduced placental size, chronic maternal hypoxia, or uterine ischemia. Although all these maternal factors can contribute to developmental toxicity, they do not necessarily occur as isolated events. Some developmental toxicants exert deleterious effects within both the embryo and the maternal system.

Animals↗